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==Overview==
==Overview==
Thienopyridines such as [[clopidogrel]] and [[ticlopidine]] selectively inhibit ADP-induced platelet aggregation and are used in patients with significant risk of arterial thrombosis as an alternative to [[aspirin]].
Thienopyridines, such as [[clopidogrel]] and [[ticlopidine]], selectively inhibit ADP-induced platelet aggregation and are used as an alternative to [[aspirin]] in patients with significant risk of arterial thrombosis.


==Mechanisms of benefit==
==Mechanisms of benefit==
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==Drug interactions==
==Drug interactions==
*Use of [[warfarin]] in conjunction with [[aspirin]] and/or [[clopidogrel]] is associated with an increased risk of bleeding and hence close monitoring is required.  
*Use of [[warfarin]] in conjunction with [[aspirin]] and/or [[clopidogrel]] is associated with an increased risk of bleeding and therefore, close monitoring is required.  


*Atorvastatin via ADP mediated platelet activation inhibits [[clopidogrel]].<ref name="pmid12515739">Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS et al. (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12515739 Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction.] ''Circulation'' 107 (1):32-7. PMID: [http://pubmed.gov/12515739 12515739]</ref> However, this inhibition is not observed with low dose atorvastatin (10mg).<ref name="pmid15023882">Mitsios JV, Papathanasiou AI, Rodis FI, Elisaf M, Goudevenos JA, Tselepis AD (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15023882 Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes.] ''Circulation'' 109 (11):1335-8. [http://dx.doi.org/10.1161/01.CIR.0000124581.18191.15 DOI:10.1161/01.CIR.0000124581.18191.15] PMID: [http://pubmed.gov/15023882 15023882]</ref>
*Atorvastatin via ADP mediated platelet activation inhibits [[clopidogrel]].<ref name="pmid12515739">Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS et al. (2003) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=12515739 Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction.] ''Circulation'' 107 (1):32-7. PMID: [http://pubmed.gov/12515739 12515739]</ref> However, this inhibition is not observed with low dose atorvastatin (10mg).<ref name="pmid15023882">Mitsios JV, Papathanasiou AI, Rodis FI, Elisaf M, Goudevenos JA, Tselepis AD (2004) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=15023882 Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes.] ''Circulation'' 109 (11):1335-8. [http://dx.doi.org/10.1161/01.CIR.0000124581.18191.15 DOI:10.1161/01.CIR.0000124581.18191.15] PMID: [http://pubmed.gov/15023882 15023882]</ref>
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==Supportive trial data==
==Supportive trial data==
*The '''CAPRIE''' trial, <ref name="pmid8918275"> (1996) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8918275 A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.] ''Lancet'' 348 (9038):1329-39. PMID: [http://pubmed.gov/8918275 8918275]</ref> involving 19,185 patients showed a modest difference in the effectiveness between [[clopidogrel]] and [[aspirin]].The relative risk reduction of 8.7% favours [[clopidogrel]] therapy among patients with established [[atherosclerotic]] vascular disease in reducing the combined risk of [[ischemic stroke]], [[myocardial infarction]] and vascular death.
*The '''CAPRIE''' trial, involving 19,185 patients showed a modest difference in the effectiveness between [[clopidogrel]] and [[aspirin]]. The relative risk reduction of 8.7% favors [[clopidogrel]] therapy among patients with established [[atherosclerotic]] vascular disease in reducing the combined risk of [[ischemic stroke]], [[myocardial infarction]] and vascular death.<ref name="pmid8918275"> (1996) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=8918275 A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee.] ''Lancet'' 348 (9038):1329-39. PMID: [http://pubmed.gov/8918275 8918275]</ref>


*The '''CURE trial''', <ref name="pmid11519503">Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK et al. (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11519503 Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.] ''N Engl J Med'' 345 (7):494-502. [http://dx.doi.org/10.1056/NEJMoa010746 DOI:10.1056/NEJMoa010746] PMID: [http://pubmed.gov/11519503 11519503]</ref> involving 12,562 patients demonstrated the efficacy and safety of adding [[clopidogrel]] (a loading dose of 300 mg, followed by 75 mg daily) to [[aspirin]] in the long-term management of patients with [[acute coronary syndromes]] without ST-segment elevation.
*The '''CURE trial''', <ref name="pmid11519503">Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK et al. (2001) [http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&retmode=ref&cmd=prlinks&id=11519503 Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation.] ''N Engl J Med'' 345 (7):494-502. [http://dx.doi.org/10.1056/NEJMoa010746 DOI:10.1056/NEJMoa010746] PMID: [http://pubmed.gov/11519503 11519503]</ref> involving 12,562 patients demonstrated the efficacy and safety of adding [[clopidogrel]] (a loading dose of 300 mg, followed by 75 mg daily) to [[aspirin]] in the long-term management of patients with [[acute coronary syndromes]] without ST-segment elevation.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [4] Phone:617-632-7753; Associate Editor(s)-In-Chief: Cafer Zorkun, M.D., Ph.D. [5]; John Fani Srour, M.D.; Jinhui Wu, M.D.; Lakshmi Gopalakrishnan, M.B.B.S.

Overview

Thienopyridines, such as clopidogrel and ticlopidine, selectively inhibit ADP-induced platelet aggregation and are used as an alternative to aspirin in patients with significant risk of arterial thrombosis.

Mechanisms of benefit

  • Clopidogrel is a thienopyridine derivative which prevents adenosine diphosphate–mediated activation of platelets by selectively and irreversibly inhibiting the binding of adenosine diphosphate to its platelet receptors and thereby blocking adenosine diphosphate–dependent activation of the glycoprotein IIb/IIIa complex.
  • Ticlopidine, another thienopyridine derivative, decreases platelet function in patients with stable angina but, unlike aspirin, has not been shown to decrease adverse cardiovascular events.

Indication

Clopidogrel is used in patients with contraindication to aspirin or aspirin intolerance.

Drug interactions

  • Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with an increased risk of bleeding and therefore, close monitoring is required.
  • Atorvastatin via ADP mediated platelet activation inhibits clopidogrel.[1] However, this inhibition is not observed with low dose atorvastatin (10mg).[2]

Adverse effects

  • Clopidogrel:
  • Gastrointestinal bleed
  • Active bleeding
  • Ticlopidine:

Supportive trial data

  • The CURE trial, [4] involving 12,562 patients demonstrated the efficacy and safety of adding clopidogrel (a loading dose of 300 mg, followed by 75 mg daily) to aspirin in the long-term management of patients with acute coronary syndromes without ST-segment elevation.
  • The CHARISMA trial, [5] a randomized placebo controlled study involving 2,163 patients reported dual anti platelet therapy with clopidogrel plus aspirin was not significantly effective in comparison to aspirin alone in reducing the rate of myocardial infarction, stroke, or cardiovascular death in patients with established vascular disease or at high risk for developing vascular disease.

ACC/AHA Guidelines- Pharmacotherapy to Prevent MI and Death and Reduce Symptoms (DO NOT EDIT) [6][7][8]

“

Class I

1. Use of warfarin in conjunction with aspirin and/or clopidogrel is associated with an increased risk of bleeding and should be monitored closely. (Level of Evidence: B)

Class IIa

1. Clopidogrel when aspirin is absolutely contraindicated. (Level of Evidence: B)

”

ESC Guidelines- Pharmacological therapy to improve prognosis in patients with stable angina (DO NOT EDIT) [9]

“

Class IIa

1. Clopidogrel as an alternative antiplatelet agent in patients with stable angina who cannot take aspirin (e.g. aspirin allergic). (Level of Evidence: A)

”

Vote on and Suggest Revisions to the Current Guidelines

Sources

  • The ACC/AHA/ACP–ASIM Guidelines for the Management of Patients With Chronic Stable Angina [6]
  • TheACC/AHA 2002 Guideline Update for the Management of Patients With Chronic Stable Angina [7]
  • Guidelines on the management of stable angina pectoris: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology [9]
  • The 2007 Chronic Angina Focused Update of the ACC/AHA 2002 Guidelines for the Management of Patients With Chronic Stable Angina [8]

References

  1. ↑ 1.0 1.1 Lau WC, Waskell LA, Watkins PB, Neer CJ, Horowitz K, Hopp AS et al. (2003) Atorvastatin reduces the ability of clopidogrel to inhibit platelet aggregation: a new drug-drug interaction. Circulation 107 (1):32-7. PMID: 12515739
  2. ↑ Mitsios JV, Papathanasiou AI, Rodis FI, Elisaf M, Goudevenos JA, Tselepis AD (2004) Atorvastatin does not affect the antiplatelet potency of clopidogrel when it is administered concomitantly for 5 weeks in patients with acute coronary syndromes. Circulation 109 (11):1335-8. DOI:10.1161/01.CIR.0000124581.18191.15 PMID: 15023882
  3. ↑ (1996) A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). CAPRIE Steering Committee. Lancet 348 (9038):1329-39. PMID: 8918275
  4. ↑ Yusuf S, Zhao F, Mehta SR, Chrolavicius S, Tognoni G, Fox KK et al. (2001) Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N Engl J Med 345 (7):494-502. DOI:10.1056/NEJMoa010746 PMID: 11519503
  5. ↑ Hankey GJ, Johnston SC, Easton JD, Hacke W, Mas JL, Brennan D et al. (2011) Effect of clopidogrel plus ASA vs. ASA early after TIA and ischaemic stroke: a substudy of the CHARISMA trial. Int J Stroke 6 (1):3-9. DOI:10.1111/j.1747-4949.2010.00535.x PMID: 21205234
  6. ↑ 6.0 6.1 Gibbons RJ, Chatterjee K, Daley J, Douglas JS, Fihn SD, Gardin JM et al. (1999) ACC/AHA/ACP-ASIM guidelines for the management of patients with chronic stable angina: executive summary and recommendations. A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Patients with Chronic Stable Angina). Circulation 99 (21):2829-48. [1] PMID: 10351980
  7. ↑ 7.0 7.1 Gibbons RJ, Abrams J, Chatterjee K, Daley J, Deedwania PC, Douglas JS et al. (2003) ACC/AHA 2002 guideline update for the management of patients with chronic stable angina--summary article: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Chronic Stable Angina). Circulation 107 (1):149-58.[2] PMID: 12515758
  8. ↑ 8.0 8.1 Fraker TD, Fihn SD, Gibbons RJ, Abrams J, Chatterjee K, Daley J et al. (2007)2007 chronic angina focused update of the ACC/AHA 2002 Guidelines for the management of patients with chronic stable angina: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines Writing Group to develop the focused update of the 2002 Guidelines for the management of patients with chronic stable angina. Circulation 116 (23):2762-72.[3] PMID: 17998462
  9. ↑ 9.0 9.1 Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F; et al. (2006). "Guidelines on the management of stable angina pectoris: executive summary: The Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology". Eur Heart J. 27 (11): 1341–81. doi:10.1093/eurheartj/ehl001. PMID 16735367.

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